Carpal tunnel syndrome (CTS) is the most frequently occurring peripheral nerve entrapment disorder (median nerve at the wrist) and is also one of the most prevalent modern-age upper limb musculoskeletal disorders. Despite its prevalence, the exact etiology and pathophysiology underlying CTS is unclear at this time.This project will address these gaps in knowledge and contribute to furthering our understanding of disease mechanism, and thereby improve the overall clinical care of patients with CTS by offering preventive measures or alternative therapeutic strategies. The proposed study is novel for the CTS field, and represents the largest natural history study incorporating the state-of-the-art high-resolution ultrasound (HRUS) and electrodiagnosis/electromyography (EDX) methodologies. We will follow a cohort of females and males with idiopathic CTS using a prospective natural history study design with 6 weeks of 'standard-of-care' conservative wrist splint treatment, and follow up for 12 months with the following aims. Aim 1: To determine and compare the baseline HRUS characteristics in females with and without idiopathic CTS (adjusted for age and BMI), and in males with and without idiopathic CTS (adjusted for age and BMI). Aim 2: To determine and compare by sex the ability of novel HRUS characteristics and patient-reported outcome measures in CTS to detect treatment effect changes between the pre- and post-treatment in men and women after 6 weeks of standard nocturnal neutral wrist splint treatment; and evaluate for correlation with other traditional measures of CTS severity and progression (as measured by hand diagram, sensibility testing, provocative maneuvers, and EDX parameters). Aim 3: To determine and compare the patient characteristics (age, sex, BMI, wrist anthropometrics, job-related risk factors), health-related quality of life measures, and clinical measures for CTS severity (physical measures, electrodiagnostic and sonographic parameters) in relation to short- and long-term outcomes in idiopathic CTS. RELEVANCE (See instructions): Establishment of standardized high-resolution ultrasound methodologies and determination of test capabilities in the diagnosis and monitoring of carpal tunnel syndrome will have important impact not only in health care of individuals with carpal tunnel syndrome but will also have far-reaching implications of reduced healthcare cost to society and increased economic productivity.